Colorectal cancer affects 148,300 patients in the United States annually (72,600 males and 75,700 females) causing 56,600 deaths each year. Those patients who have two or more first-and/or second-degree relatives with colorectal cancer have a potentially definable inheritable disorder. Approximately 5–6% of colorectal cancers have a known germline genetic mutation. Hereditary nonpolyposis colon cancer (HPNCC) is one of the syndromes and accounts for 3% of newly diagnosed colorectal cancer cases. HNPCC is characterized by the early onset of colorectal cancer (mean age, 45 years), with multiple generations affected. These cancers tend to be proximal to the splenic flexure, poorly differentiated, and have an increased frequency of synchronous and metachronous cancers. There is also an excess of extracolonic cancers, including endometrial, ovarian, gastric, small bowel, hepatobiliary, and transitional cell carcinomas. Over a patient’s lifetime, there is an 80% risk of cancer, with colon cancer being the most frequently diagnosed cancer. The syndrome is characterized by an autosomal dominant mode of inheritance. Germline mutations in mismatch repair (MMR) genes, which normally repair mistakes in DNA replication, are responsible for HNPCC.